Longer lived PET radioisotopes are widely recognized to play a growingly significant role in radioimmunoimaging protocols. Such protocols are needed for patient selection and assessment of response to immunotherapies, which are poised to become the backbone of all cancer treatment regimens. Such radioimmunoimaging protocols, also called “immuno-PET,” have eluded translation into clinical practice due to the mismatch in pharmacokinetics of routine PET isotopes such as fluorine-18 with immunotherapies, such as antibodies. Large-scale, economical, reliable production of the longer-lived PET radioisotopes zirconium-89, iodine-124, and copper-64 is a long-standing problem. For many years, various researchers at different laboratories have employed compact cyclotrons using solid phase targets in the quest to supply clinically significant quantities of these isotopes. Such small-scale production is not economically attractive. The high costs of these methods are reflected in the scarcity and high prices. These are widely recognized barriers for clinical translation of immuno-PET into the standard of care.
Centralized, economical, large-scale production is cited as a critical need by the National Cancer Institute in a review article by T. Nayak and M. W. Brechbiel (“Radioimmunoimaging with Longer-Lived Positron-Emitting Radionuclides: Potentials and Challenges,” Bioconj. Chem., 20(5): 825-841, May 20, 2009). In an authoritative review publication by sixteen radioisotope production experts for the International Atomic Energy Agency (IAEA), the reason given for the limited support for such large-scale production by the radiopharmaceutical industry is its being viewed as technically not achievable (“Cyclotron Produced Radionuclides: Emerging Positron Emitters for Medical Applications: 64Cu and 124I,” IAEA Radioisotopes and Radiopharmaceuticals Report No. 1, March 2016). The IAEA report's authors call for the development of high-current, high-power acceptance targets. By accelerator physics convention, the term high-current refers to multi-milliampere beam current (A. W. Chao, et al. “Handbook of Accelerator Physics and Engineering,” World Scientific, 2013). This convention applies to all references herein.
Commercial cyclotrons presently available for production of longer-lived isotopes push the limits of current, up to ˜1 mA, according to A. W. Chao, et al. (“Handbook of Accelerator Physics and Engineering,” World Scientific, 2013). The azimuthally varying field (AVF) cyclotron, with magnetic field on hills and valleys—the industrial “deep valley” design—is the present state-of-the-art for PET and single-photon emission computed tomography (SPECT) isotope production. The deep valley field provides the necessary strong focusing and small beam size.
The resonant family of particle accelerators is comprised of cyclotrons, linacs, and synchrotrons. As multi-pass accelerators, cyclotrons achieve their final energy by circulating the charged particle beam in isochronous orbits several hundred times through an accelerating gradient generated by a single radio-frequency (RF) cavity in resonance. Operationally, RF amplifier power faults are one of the most common failure modes for resonant accelerators. Having just one RF cavity for acceleration, cyclotrons cannot be made fault-tolerant.
Cyclotrons are limited to simultaneous irradiation of dual targets, a significant restriction on scalability. Cyclotron target power acceptance has a ceiling of ˜2 kW. Beam windows, typically titanium or gridded aluminum, deliver a multiply-scattered, Gaussian beam profile to the dual targets. The use of non-linear focusing, i.e., octupole magnetic fields, to “flat-top” the Gaussian beam is an intractable problem, as existing cyclotron facilities have been built in such a manner as to preclude proper placement of the octupoles. Irradiation of solid phase targets is performed by “rastering” the Gaussian beam-sweeping the beam back-and-forth and up-and-down the face of the target plate using active beamline elements (magnets). This limits the time the peak power density is incident of any portion of the target substrate material to minimize the potential for damage due to melting.
High-brightness H− ion source development solved many of the thermal, mechanical, and radio-activation problems associated with cyclotron dual beam extraction. Most compact cyclotron designs use an internal ion source, suited only for low to moderate beam currents-150 to 300 μA. Internal ion sources place many constraints on the design of a new cyclotron central region, making beam matching, bunching, and manipulation impossible. An internal ion source places a gas leak directly into the cyclotron, which is bad for negative ions such as H− and raises vacuum requirements.
An external ion source is required for multi-milliampere beam currents. These are incorporated into the higher-energy cyclotrons used for production of longer-lived isotopes referenced by A. W. Chao. External ion sources are used in the industry's flagship cyclotrons, e.g., the Advanced Cyclotron Systems, Inc. (ACSI) TR-30, making 90% of the thallium-201, iodine-123, gallium-67, and indium-111 supplied in North America, with its 1.2 mA rating, and the Ion Beam Applications (IBA), S. A., Cyclone 30 VHC cyclotron, also rated at 1.2 mA.
Recent data support the inference that cyclotrons are not a viable technology platform for true high-current targets as they have reached their technology limit at 3 mA. Study data compiled by R. A. Baartman of H− cyclotron design at TRIUMF using the ACSI TR30/CRM model determined that fundamental limits on beam current exist due to space charge effects, both transverse and longitudinal (“Intensity Limits in Compact H− Cyclotrons,” Proc. 14th Intl. Conf. on Cyclotrons and their Applications, Cape Town, South Africa, 2013). Space charge reduces vertical focusing, placing an upper limit on instantaneous current. Longitudinal space charge reduces acceptance as well as average current per the author. These limits cannot be economically overcome. The author's data and derived relation predict an upper limit on beam current extracted (Iextr) from the TR30 cyclotron of 3.3 mA for an injected current (Iinj) of 30 mA:
      I    extr    =                    I        inj            5        ⁡          [                        (                                    60              ⁢                                                          ⁢              mA                        -                          I              inj                                )                          54          ⁢                                          ⁢          mA                    ]      The current record of 3 mA is held by the TR30/CRM at TRIUMF. Due to the unavoidable losses of 20% of extractable beam current on each of the cyclotron's two target beamline collimators, multi-millampere target currents are not obtainable. The engineering solution is an uneconomical dramatic increase (>44%) in cyclotron size, driving a further need for more heavy concrete for the machine vault, and a corresponding increase in decommissioning costs. Even with external ion sources, cyclotron technology has fundamental limits on beam current due to space charge, which have hampered the development of high-current targets for large-scale iodine-124, copper-64, and zirconium-89 production.
The capability to accelerate H− ions at higher intensities, at low emittance, than is presently available will contribute to isotope production. For high beam currents in the range of 10-200 mA, a radio frequency quadrupole (RFQ) is one of the required accelerating structures. Linear accelerators (linacs), employing RFQs in their design, represent one of the main technologies for the acceleration of charged particles (atomic ions) from a source (ion source) to the desired final energy. A 14 MeV proton beam is optimal for production of zirconium-89, copper-64, and iodine-124 via their respective high-purity, proton-neutron exchange nuclear reactions:89Y(p,n)89Zr,64Ni(p,n)64Cu,and124Te(p,n)124I.The needs of the first two target materials are quite different from the third: yttrium-89 and nickel-64 are representative metallic target substrates, while the tellurium-124 enriched TeO2 is a low thermal conductivity oxide. Tellurium-124 enriched oxide is preferred over metallic tellurium-124 for iodine-124 manufacture. The former requires only thermo-chromatographic separation (“dry distillation”) of the iodide oxidation species, while the latter involves arduous wet chemical processing. Both metallic and low thermal conductivity target variants benefit from a constant proton fluence rate on the target plate. It is essential for the latter target variant to avoid thermal shocks and consequent losses of expensive enriched material (e.g., tellurium-124) during irradiations at high power acceptance. Thus, two high power target station variants are warranted for longer-lived PET isotope production, and a constant proton fluence rate is highly advantageous for low production costs.
A high-duty-factor linac is necessary to avoid the high peak currents associated with the Alvarez drift-tube linac (DTL). For a high-duty-factor-here 100%, or continuous-wave (CW)—linac, the cooling of the RFQs and downstream accelerating structures' copper cavities becomes an important engineering constraint. This reflects one of the disadvantages of normal conducting (or room temperature) copper-cavity linacs: the large radio frequency (RF) power required due to ohmic dissipation in the cavity walls. As a result, both RF power amplification and AC power for operations are major costs for a copper cavity CW ion linac.
New linac designs are evaluated for application of superconducting RF cavities for their advantages over normal conducting copper cavities. The use of superconducting niobium cavities allows for a reduction in RF surface resistance on the order of 105 when compared with room temperature copper. Therefore, application of superconducting RF cavities (SCRF) as linac accelerating structures is recognized as offering better performance and lower AC power and RF power costs. Some of this gain in reduced surface resistance is offset by the inefficiency of cryogenic refrigeration for liquid helium at 4 K or below with superconducting RF cavities of niobium. Another disadvantage is the significantly increased cost and complexity of a superconducting linac, with less advantage in lower RF power costs for low-β (0.1-0.2 in units of the velocity of light) applications.
U.S. Pat. No. 6,777,893, entitled “Radio Frequency Focused Interdigital Linear Accelerator,” to Swenson, introduced an RF focused interdigital linac, or “RFI” accelerating structure as the basis for a normal conducting copper cavity linac. This structure incorporates RF focusing into the drift tubes of an interdigital linac structure which is more compact and energy efficient. It has been used, also by Swenson, to extend the performance of a proton RFQ linac structure to 2.5 MeV for the Boron Neutron Capture Therapy (BNCT) application. For the application of longer lived PET radioisotope production, it is useful to extend the performance of the RFQ to 14 MeV. The RFI linac is ten times more efficient than the RFQ in the 6-14 MeV energy range. Furthermore, it is desirable to scale the RF power amplification in modular fashion. Since the linac is a single-pass accelerator, fault-tolerance for reliability in operations may be engineered into a PET radioisotope system based on the CW ion linac.
Economical scalability requires the simultaneous delivery of high current proton beams to multiple high-power acceptance isotope production targets from a single particle accelerator. However, splitting a high current proton beam between multiple targets to deliver a constant proton fluence rate on the target plate while preserving parent beam parameters is an intractable problem. This requires negative ions for extraction of target current by charge-exchange reactions. Thus, a high-brightness H− ion source must undergo matching of the injected beam ellipse to the focusing system of the RFQ. The RFI linac structure of Swenson can accommodate acceleration and focusing of negative ions by shifting the phase of all fields by one half cycle. The subsequent beam splitting operation should preserve the parameters of the parent beam, including size, divergence, energy, energy spread, and phase spread. Y. Liu (“Laser Wire Beam Profile Monitor in the Spallation Neutron Source (SNS) Superconducting Linac,” Nucl. Inst. Meth. Phys. Res. A612, 241-153, 2010) describes a laser-photo-detachment (“laser-wire”) method that has been put in practice at the Oak Ridge National Laboratory's Spallation Neutron Source (SNS) for beam diagnostics applications on the 1 GeV superconducting H− linac to parasitically monitor beam parameters. In units of the velocity of light, the SNS H− linac has β=0.875. A CW ion linac for long-lived PET radioisotope production of iodine-124 and zirconium-89 has β=0.1734 for 14 MeV protons.
Following this, beam manipulation by a non-linear focusing magnet in a lattice arrangement could reduce the peak power density for achieving higher power acceptances. This would result in “flat-topping” the Gaussian beam profile to deliver a constant proton fluence rate on the target plate. This delivers the so-called Waterbag beam profile. Beam uniformization to the Waterbag profile substantially reduces the peak power density, allowing much higher beam currents and higher power acceptance without risk of target damage by approaching any of the melting points of the target plate or deposited substrate undergoing irradiation, the latter often comprised of expensive enriched stable isotopes.
As a beam window between the incident proton beam and target plate results in a multiply-scattered, Gaussian beam profile, high-power acceptance targets must be present in a “windowless” configuration to use the Waterbag beam distribution. This configuration eliminates the typical grid-supported aluminum foil which provides both a vacuum boundary and a seal for chilled helium gas cooling on the face of the target plate common to solid phase cyclotron targets.
For high-power acceptance, target cooling systems must handle high incident heat fluxes, exceeding 1 kW/cm2, to achieve large-scale production capacity. This heat flux represents the practical limit of water cooling technology. The use of high-velocity water jets for cooling targets at 1 kW/cm2 is suited only for small targets. For the large metallic targets of the present invention, conditions will exceed the critical heat flux (CHF) limit for water cooling (500 W/cm2). Beyond this limit, heat flow is unstable, vapor blankets the heated surface of the back of the target plate, and temperatures jump to very large values. This heat flow regime is governed by film boiling and radiative transfer, called burnout.
The replacement of water as the coolant working fluid with a eutectic Ga—Sn alloy offers substantial heat transfer benefits with few drawbacks. Eutectic Ga—Sn alloy offers fifty times better thermal conductivity than water with linear heat removal all the way up to its boiling point of 1200° C. However, gallium is compatible with target materials such as stainless-steel, titanium, and elastomers, but corrodes aluminum. The target plate irradiation capsule, or “rabbit,” must be an aluminum exclusion zone. Above 300° C., desirable metals are limited to cobalt, chromium, titanium, tantalum, niobium, molybdenum, rhenium, and tungsten. With appropriate materials selection, the high-power acceptance target provides sufficient cooling margin to protect against reaching any target material melting points. Together, beam uniformization and cooling capacity margin of safety prevent unacceptable losses of the aforementioned enriched target materials.